An Editorial in Nature this week highlights three studies of a sex bias in biomedical research.

And yet, despite the obvious relevance of these sex differences to experimental outcomes, three articles in this issue (see pages 688, 689 and 690) document that male research subjects continue to dominate biomedical studies. Some 5.5 male animal models are used for every female in neuroscience, for example. And apart from a few large, all-female projects, such as the Women's Health Study on how aspirin and vitamin E affect cardiovascular disease and cancer, women subjects remain seriously under-represented in clinical cohorts. This is despite reforms undertaken in the 1990s, when sex discrimination in human trials was first widely recognized as a problem.

This reminded me of something I wrote a little while back to explore part of the reason for this bias in research models. The post originally appeared December 2, 2008.

The titular quote came from one of my early, and highly formative, experiences on study section. In the course of discussing a revised application it emerged that the prior version of the application had included a sex comparison. The PI had chosen to delete that part of the design in the revised application, prompting one of the experienced members of the panel to ask, quite rhetorically, "Why do they always drop the females?"
I was reminded of this when reading over Dr. Isis' excellent post on the, shall we say less pernicious, ways that the course of science is slanted toward doing male-based research. Really, go read that post before you continue here, it is a fantastic description.

Thank you. That's the first time I've seen someone address the reasons behind ongoing gender disparities in health research. I still can't say as it thrills me (or you, obviously), but I understand a bit better now.

Did somebody ring?
As I pointed out explicitly at least once, research funding has a huge role in what science actually gets conducted. Huge. In my book this means that if one feels that an area of science is being systematically overlooked or minimized, one might want to take a close look at the manner by which science is funded and the way by which science careers are sustained as potential avenues for systematic remedy.

Funding

There are a couple of ways in which the generalized problems with NIH grant review lead to the rhetorical comment with which I opened the post. One very common StockCritique of NIH grant review is that of an "over ambitious" research plan. As nicely detailed in Isis' post, the inclusion of a sex comparison doubles the groups right off the bat but even more to the point, it requires the inclusion of various hormonal cycling considerations. This can be as simple as requiring female subjects to be assessed at multiple points of an estrous cycle. It can be considerably more complicated, often requiring gonadectomy (at various developmental timepoints) and hormonal replacement (with dose-response designs, please) including all of the appropriate control groups / observations. Novel hormonal antagonists? Whoops, the model is not "well established" and needs to be "compared to the standard gonadectomy models", LOL >sigh<.Grant reviewers prefer simplicityKeep in mind, if you will, that there is always a more fundamental comparison or question at the root of the project, such as "does this drug compound ameliorate cocaine addiction?" So all the gender comparisons, designs and groups need to be multiplied against the cocaine addiction/treatment conditions. Suppose it is one of those cocaine models that requires a month or more of training per group? Who is going to run all those animals ? How many operant boxes / hours are available? and at what cost? Trust me, the grant proposal is going to take fire for "scope of the project".
Another StockCritique to blame is "feasibility". Two points here really. First is the question of Preliminary Data- of course if you have to run more experimental conditions to establish that you might have a meritorious hypothesis, you are less likely to do it with a fixed amount of pilot/startup/leftover money. Better to work on preliminary data for two or three distinct applications over just one if you have the funds. Second aspect has to do with a given PIs experience with the models in question. More opportunity to say "The PI has no idea what s/he is doing methodologically" if s/he has no prior background with the experimental conditions, which are almost always the female-related ones. As we all know, it matters little that the hormonal assays or gonadectomy or whatever procedures have been published endlessly if you don't have direct evidence that you can do it. Of course, more latitude is extended to the more-experienced investigator....but then s/he is less likely to jump into gender-comparisons in a sustained way in contrast to a newly minted PI.
Then there are the various things under grantspersonship. You have limited space in a given type of grant application. The more groups and comparisons, the more you have to squeeze in with respect to basic designs, methods and the interpretation/alternative approaches part. So of course you leave big windows for critiques of "hasn't fully considered...." and "it is not entirely clear how the PI will do..." and "how the hypothesis will be evaluated has not been sufficiently detailed...".

Career

Although research funding plays a huge role in career success, it is only part of the puzzle. Another critical factor is what we consider to be "great" or "exciting" science in our respective fields.The little people can fill in the details. This is basically the approach of GlamourMagz science. (This is a paraphrase of something the most successful GlamourMagz PI I know actually says.) Cool, fast and hot is not compatible with the metastasizing of experimental conditions that is an inevitable feature of gender-comparison science. Trouble is, this approach tends to trickle down in various guises. Lower (than GlamourMag) impact factor journals sometimes try to upgrade by becoming more NS-like (Hi, J Neuro!). Meticulous science and exacting experimental designs are only respected (if at all) after the fact. Late(r) in someone's career they start getting props on their grant reviews for this. Early? Well the person hasn't yet shown the necessity and profit for the exhaustive designs and instead they just look...unproductive. Like they haven't really shown anything yet.
As we all know splashy CNS pubs on the CV trump a sustained area of contribution in lower journals six ways to Sunday. This is not to say that nobody will appreciate the meticulous approach, they will. Just to say that high IF journal pubs will trump. Always.
So the smart young PI is going to stay away from those messy sex-differences studies. Everything tells her she should. If he does dip a toe, he's more likely to pay a nasty career price.
This is why NIH efforts to promote sex-comparison studies are necessary. Promoting special funding opportunities are the only way to tip the equation even slightly more favorable to the sex-differences side. The lure of the RFA is enough to persuade the experienced PI to write in the female groups. To convince the new PI that she might just risk it this one time.
My suspicion is that it is not enough. Beyond the simple need to take a stepwise approach to the science as detailed by Isis, the career and funding pressures are irresistible forces.

You're singing my song, Drug Monkey. Thanks so much for re-posting this--I hadn't seen the original.
I am so pleased that Nature published these opinion pieces (and particularly pleased that they came out before UC drops its NPG subscription!). So many mental illnesses and neurodegenerative disorders are differently prevalent in men vs. women, and studies of sex differences in the lab can help identify mechanisms of both vulnerability and resilience. Amazing, though, how few people see sex disparities research as worthwhile.

Being a theoretical physicist my understanding of this is probably limited, but it sounds like an experiment with both male and female mice would be a better experiment, not just for the potential public health benefits downstream, but also better science in the pure sense: You'd know whether the phenomenon that you observed is in fact of universal significance, or only applicable in half of the species.
In physics it isn't career suicide to do a tour de force experiment that measures a known phenomenon to higher accuracy than previous work. Yeah, yeah, there's sloppy and trendy stuff everywhere, even in our best journals, but high-precision measurements with careful controls often get published in Physical Review Letters and other top journals. Conversely, it sounds like the biomedical community would chew up and spit out anybody who spent "too much time" on the really careful experiments that determine whether the result applies to half of the species or all of the species.
I'm not going to claim that physics is perfect. God knows there's a lot of junk. But there also seems to be a place in the field for the high-precision carefully-controlled tour de force experiment. I don't know that we're any better at keeping garbage out, but at least we seem to have some room for people who want to make a career of doing things in a really, really careful way, even if it does take time.
I'll often look at an issue of Physical Review Letters and see abstracts that go "Although this fundamental law of physics has been known for 150 years and tested to 11 decimal places, we decided to do a measurement to 12 decimal places, just to be sure. And, yep, that law is still true." I'm guessing that if I looked in Cell I would never see an abstract that goes "Because so much work hinges on this particular phenomenon, we decided to do an experiment with 100x as many mice as any previous study, and both genders, just to see if there were any discrepancies that got overlooked in studies with smaller and less representative samples. And, yep, the result still holds."
Now, before anybody waves the dirty laundry of physics in my face, I'm well aware that it's there. We don't do a good job of getting rid of it, but at least we seem to make room for people who want to do better than that. I'm not here to look down on biomedical people, because I know there are plenty of people who care enough to do the good experiments, but it does seem like there's a uniquely awful pressure cooker environment, and I feel sorry for you guys.

This reinforces my nervousness - I just submitted a grant in which I plan to use male and (intact) female mice in parallel. If there's a difference, it's pilot data for the next series of experiments using ovx/stage of estrous cycle/etc in the females for mechanistic studies. The stage of cycling is unlikely to affect the treatment since it's a chronic manipulation.
I'm worried I'm going to get slammed by reviewers for including females at all, due to all of the abovementioned issues, but the human disease is highly dimorphic, with a 2:1 ratio of female:males.
So what do I do? Take out the females? Because I cannot (scope! time! N!) propose all the hormonal controls in the timeframe.
But if there is a sex difference (which my pilot data suggests there is), then isn't it important to have solid data on what those differes are before looking the role of hormones?
And if I want to compare males and females later, then that would mean running the experiments with males again. Isn't that a huge waste of time, animals, and resources?

Because so much work hinges on this particular phenomenon, we decided to do an experiment with 100x as many mice as any previous study, and both genders, just to see if there were any discrepancies that got overlooked in studies with smaller and less representative samples. And, yep, the result still holds."

...thanks for the ROFL.
Natalie-
sorry, don't meant to enhance your nervousness. and of course everything has tradeoffs. You may be exposing yourself to a bit of StockCritique bait (which is not inevitably hit, btw) in order to significantly enhance the imact, relevance and general interest factor. You had good reasons for wanting to do the sex comparison, so you just have to make your best arguments and hope to convince the reviewers.
and remember, if you DO get a review that forces you to take the female comparison out of the revised application...(all together now) "a grant is not a contract". I.e., do whatever you think is most important once you get the award.

I would also like to point out that, in addition to gender, most experiments are done with a single age group. Most rodent experiments begin with animals that would be classified as late adolescents or young adults. Why? Because they are weaned, mature enough to breed, and waiting any longer costs more.
Children have also been excluded from clinical research over the years for a variety of reasons (some good, some bad), and the elderly may also not have opportunities.
We need to understand it ALL. I am afraid that we won't have that opportunity until funding opens up a bit.
That, or we all have to be 70 kg young adult white males, the mainstay of research.

This is an issue that gets totally overlooked all too often, and doesn't end in the animal research realm. While NIH requires Phase III clinical trials to include an equal representation of females and males, it does not require the same of earlier trials. And, when you look at the distribution of males and females in the Phase I and II clinical trials, the numbers heavily biased to a male population. It makes me wonder how many drugs haven't made it to Phase III trials because it wasn't very effective in a male-biased population, but had the potential to therapeutic for females.
While yes, including females in both basic and clinical research makes the design a bit more complex, it's just good science, and both academia and the funding agencies should realize this and embrace it.